The rising seroprevalence of HSV-2 infection in the United States combined with the shift in the age of acquisition of HSV-1 from childhood to early adulthood has resulted in a continuing increase in neonatal HSV infections. Despite a remarkable increase in the rate of cesarean sections among mothers with recurrent genital herpes, neonatal herpes occurs in 1 in early 2,000 live births at our institution. Much of this dichotomy appears due to the fact that the vast majority of cases of neonatal herpes are associated with the acquisition of HSV at or near the time of delivery. HSV seroconversion which is completed by the time of labor does not appear to be associated with an increase in adverse pregnancy outcome nor does exposure of the infants to HSV-2 from an HSV-2 seropositive mother. This delineation of the morbidity of HSV to the late pairs of pregnancy allows one to develop strategies to 1) reduce the acquisition of HSV among susceptible women, and 2) reduce the morbidity of excess cesarean sections among women who are HSV-2 seropositive. The specific aims of this project are to 1) define the virological and obstetrical factors associated with perinatal maternal-fetal transmission of HSV, 2) to initiate phase I/II studies among serologically discordant couples to reduce the frequency of acquiring HSV during the third trimester of pregnancy. 3) to define strategies to reduce the frequency of caesarean section among women with symptomatic recurrent genital herpes at the time of labor. Studies to further define the association between viral load is measured by quantitative PCR and role of type specific (HSV-2) versus heterologous (HSV-1) antibodies in decreasing the transmission of HSV-2 to the neonate will be conducted. To reduce seroconversion in the late third trimester, a randomized controlled trial to compare counseling, versus counseling plus treatment of the male HSV-2 seropositive acyclovir administered from 36 weeks to the onset of labor among women with a history of symptomatic recurrent genital herpes to reduce the frequency of cesarean section and to assess the role suppressive acyclovir has on reducing subclinical reactivation of HSV as detected by PCR. These studies are directed at initiating attempts to reduce the transmission of neonatal herpes and reduce the morbidity of standard medical obstetrical care worldwide. The program involves a collaboration between the University of Washington, the University of British Columbia and Madigan Army Hospital.